The mesolimbic dopamine (DA) system has been primarily implicated in the reinforcing effects of drugs of abuse. While this pathwayand DA signaling are the focus of most research in this area, it is also clear that norepinephrine (NE), via interactions with the dopaminergic system, plays an important role in modulating the neurochemical and behavioral responses to drugs of abuse in animal models. The enzyme dopamine (3-hydroxylase(DBH) converts DA to NE in noradrenegic cells, thus controlling the abundanceof both NE and DA in the brain. Genetic and pharmacological data in humans support an important role for DBH in modulating psychostimulant-related behaviors. First, a common polymorphism in the humanDbh gene is a critical determinant of DBH enzymatic activity and appears to influence behavioral andcognitive responses to cocaine. Second, the DBH inhibitor disulfiram (Antabuse) has shown striking promise as a treatment for cocaine dependence, yet its mechanism of action is unknown. The objective of this proposal is to determine the influence of DBHactivity on catecholamine neurochemistry and cocaine-related behaviors, including sensitization, reward, aversion, and relapse, and to understand why disulfiram administration results in cocaine abstinence in dependent humans. This will be accomplished by using a combination of genetics (Dbh knockout mice), and pharmacology (disulfiram). Completion of the aims in this proposalwill contribute to our understanding of how the interaction between noradrenergic and dopaminergic systemsinfluences drug addiction and the mechanism of disulfiram- induced cocaine abstinence, and will suggest novel treatments for psychostimulant dependence.